This invention relates to a certain group of new 4-phenylphthalazine derivatives, a process for preparing the same and their use as pharmaceuticals.
The compounds of this invention are a novel class of the 1-alkylamino-4-phenylphthalazine derivatives and pharmaceutically acceptable salts thereof and show valuable therapeutic activities, especially activity to improve or ameliorate circulatory disorders or dysfunctions.
In the prior art, there have been proposed in British Pat. No. 1,303,061 a series of 1-alkylamino-4-phenylphthalazine derivatives having the formula ##STR1##
In said British Patent, there are illustratively disclosed as R.sub.1 a methyl, ethyl, n-propyl, isopropyl, isobutyl or hexyl group; however, only the version "amyl group" is disclosed therein for an alkyl group having 5 carbon atoms and no concrete disclosure is seen with regard to its isomerism. Moreover, said British Patent discloses that the derivatives have an anti-inflammatory activity, but it does not disclose or teach any other pharmacological activities of the derivatives. Further, it is disclosed in said British Patent that the compounds having the above formula wherein the substituent R.sub.1 is an alkyl group having 1 to 4 carbon atoms are preferable of those compounds (said British Patent Specification, page 2, left column, line 34), but it is to be noted that an alkyl group having 5 carbon atoms, namely an amyl group is clearly excluded from the preferred perview of groups for R.sub.1. On the other hand, there are disclosed in J. Med. Chem., 12, 555 (1969) those compounds of the above formula wherein R.sub.1 is a cyclopentyl group, together with other derivatives; however, an anti-inflammatory activity solely is disclosed therein as pharmacological activities.
For drugs or medicaments, which may be applied in prophylatic and therapeutic treatments of ischemic cardiac diseases such as myocardial infarction or angina pectoris, circulatory disorders or dysfunctions such as cerebral and peripheral circulatory disturbance in cerebral thrombosis or cerebral embolism, there should be required the activity to increase blood flow volume at the disturbed sites, the anti-thrombic activity as well as the basic activity therefor, i.e., the vasodilation activity and the activity to inhibit blood platelet aggregation. Thus, there has been desired such a compound that has all activities as noted above together. Also, as prolonged administration of drugs in necessary for prophylatic and therapeutic treatments of the aforesaid diseases, it is significant that such a type of drugs should have a lower toxicity.
As reported in "Drugs, 18, 439 (1979), many anti-inflammatory agents such as aspirin or indomethacin are known to show the activity to inhibit blood platelet aggregation, but the mode of action thereof is attributed to the action to inhibit cyclooxygenase and consequently inhibit biosynthesis of prostaglandins as seen for anti-inflammatory agents [vide, Pharmacol. Rev., 26, 33 (1974)]. Consequently, they are not desirable as a circulatory disorder improving agent, because not only thromboxane A.sub.2, a substance inducing blood platelet aggregation and vasoconstriction, but also biosynthesis of prostaglandin I.sub.2 (hereinafter referred to as "PGI.sub.2 "), which exhibits an action opposit to that of thromboxane A.sub.2 in blood platelets and blood vessels, could be simultaneously inhibited.
And yet, aspirin or indomethacin does not show at all the activity to increase blood flow ["Prostaglandins", 25, 549 (1983)] and it is further reported that indomethacin did decrease a topical blood flow in brain on the contrary [Am. J. Physiol., 243, H416, (1982)].
The present inventors previously found that some 1-anilino-4-phenylphthalazine derivatives show a potent activity to inhibit blood platelet aggregation in vitro, as seen in Japanese Patent Laid-open Application Nos. 53659/1981, 53660/1981 and 48972/1982. However, other circulatory dysfunction improving actions than the action to inhibit blood platelet aggregation are not disclosed at all in these Japanese Application.